Pharmaceutical formulations comprising proteins and peptides can be manufactured from for example granules, which are compressed into tablets, or from blends of granules and excipient(s), which are compressed into tablets. The granulation process may be carried out as a dry granulation process where granules are formed from either blends containing excipients or from blends comprising the pharmaceutical active ingredient and one or more excipients. Dry granulation may be carried out by compaction of the blend into ribbons in a roller compactor followed by milling of the ribbons. A dry granulation process may also be carried out by compression of the blend into tablets followed by milling of the tablets, i.e. slugging.
In dry granulation processes, sticking of material to either the rolls of the roller compactor used for dry granulation or to the die and punches of the tablet press used to form granules/tablets may prevent proper processing resulting in an unacceptable product quality, i.e. granule quality or tablet quality, or in an unacceptable low process yield, or in no processability at all. In order to prevent such sticking, lubricant(s) are frequently added to the blend. Lubricants may comprise magnesium stearate, stearic acid, talc, etc. It is well-known that lubrication of the blend used for dry granulation is a major cause of decreased mechanical strength and prolonged disintegration time of the final compressed tablets. Likewise lubrication of the blend for tablet compression is well known to reduce the mechanical strength of the tablets, prolong the disintegration time of the tablets, prolong the release of the pharmaceutical active ingredient from the tablet and increase tablet friability. This phenomenon is known as over-lubrication.
Over-lubrication is caused by high concentration of lubricant(s) or by long mixing time of the lubricant(s) with the remaining ingredients of the blend used for either dry granulation or tablet compression. Over-lubrication may be caused by formation of a hydrophobic layer around powders and/or granules used to manufacture the tablet leading to e.g. slower dissolution and/or poorer wetting and/or reduced binding properties. Therefore, the mixing time of the lubricant(s) has to be carefully controlled and kept at a minimum, while keeping the concentration of lubricant(s) as low as possible to prevent the undesirable effects of over-lubrication.